This is a continuation and expansion of a research program that has been supported by NIMH and NIDA for several years. The purpose is to delineate some of the pharmacological and biochemical characteristics of tolerance to the narcotic analgesics. The investigations outlined will continue work on the properties of both tolerance and dependence and explore new avenues of approach to this problem. We propose to investigate factors involved in the appearance, maintenance and loss of tolerance and physical dependence as they relate to dose, dose interval and chemical structure of the narcotic analgesic administered. We also propose to study the correlation of both tolerance and physical dependence to psychological dependence. Our approach will be both biochemical and pharmacological and we will also be studying enzyme changes which accompany tolerance and dependence. We plan to continue the investigation of possible similarities between immunological reactions and tolerance. We shall carry out these studies using analgesic assays, temperature measurements, locomotor activity measurements as well as studies to measure drug-seeking behaviour. We will use agents that affect protein synthesis and short-term memory to investigate the nature of the drug-receptor interaction in tolerance and dependence. We will continue the study of the interaction of the analgesic agonists and the antagonists, both mixed and pure, by investigating the prevention of the appearance of tolerance and dependence after the concomitant administration of the two classes of compounds. Studies of the effects of prior chronic administration of the antagonists on sensitivity to the analgesics and on tolerance and dependence will be carried out.